Causes of Neutropenia
Neutropenia is primarily caused by insufficient circulating neutrophils, inadequate myeloid marrow reserve, or congenital/acquired defects in neutrophil function, with various etiologies ranging from infections to medications, genetic disorders, and malignancies. 1
Definition and Classification
Neutropenia is defined as an absolute neutrophil count (ANC) below 1500 cells/mm³, and can be categorized by severity:
- Mild: 1000-1500 cells/mm³
- Moderate: 500-1000 cells/mm³
- Severe: <500 cells/mm³ 2
The risk of infection increases with severity of neutropenia, duration, and rate of decline in neutrophil count 3.
Major Categories of Neutropenia
1. Congenital/Inherited Neutropenia
- Genetic mutations: Most commonly in ELANE gene 4
- Inheritance patterns: Autosomal recessive, autosomal dominant, and X-linked forms 4
- Associated syndromes:
- Shwachman-Diamond syndrome (with pancreatic insufficiency)
- Glycogen storage disease type Ib
- WHIM syndrome (warts, hypogammaglobulinemia, infections, myelokathexis) 5
2. Acquired Neutropenia
Medication-Induced
- Antipsychotics: Clozapine can cause severe neutropenia, with highest risk during first 18 weeks of treatment 6
- Other medications: Chemotherapeutic agents, antibiotics, antithyroid drugs, anticonvulsants
Infection-Related
- Bacterial infections: Overwhelming bacterial sepsis
- Viral infections: Common cause of transient neutropenia
- Parasitic infections: Malaria and other parasitic diseases can cause neutropenia, especially in travelers returning from endemic areas 1
Immune-Mediated
- Autoimmune neutropenia: Primary or secondary to other autoimmune disorders
- Alloimmune neutropenia: Neonatal alloimmune neutropenia
Malignancy-Related
- Direct bone marrow infiltration: Leukemias, lymphomas, metastatic solid tumors
- Indirect effects: Paraneoplastic syndromes
- Treatment effects: Chemotherapy, radiation therapy 3
Nutritional Deficiencies
- Vitamin B12 deficiency
- Folate deficiency
- Copper deficiency
Splenic Sequestration
- Hypersplenism from various causes
Pathophysiologic Mechanisms
Neutropenia can develop through three main mechanisms:
- Decreased bone marrow production
- Increased peripheral destruction of neutrophils
- Abnormal sequestration of neutrophils 7
Clinical Consequences
The risk of infection is inversely proportional to the neutrophil count, with significant risk at counts below 500/μL and particularly high risk below 100/μL 3.
Primary sites of infection in neutropenic patients include:
- Alimentary tract (mouth, pharynx, esophagus, intestines)
- Sinuses
- Lungs
- Skin 3
Common pathogens in neutropenic patients include:
- Early infections: Gram-positive bacteria (coagulase-negative staphylococci, S. aureus, viridans group streptococci) and gram-negative bacteria (E. coli, Klebsiella, Pseudomonas aeruginosa)
- Later infections: Antibiotic-resistant bacteria, fungi (Candida, Aspergillus), and viruses 3
Diagnostic Approach
When neutropenia is detected, evaluation should include:
- Complete blood count with differential
- Examination of blood smear
- Medical and family history
- Physical examination focusing on signs of infection
- Bone marrow examination in cases of severe or persistent neutropenia 8
Common Pitfalls
- Failing to recognize drug-induced neutropenia
- Overlooking underlying causes in chronic neutropenia
- Delaying appropriate therapy in febrile neutropenia 1
In summary, neutropenia has diverse etiologies ranging from benign transient causes to life-threatening conditions requiring immediate intervention. Understanding the underlying cause is essential for appropriate management and prevention of infectious complications.